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Targeting MARCO can lead to enhanced dendritic cell motility and anti-melanoma activity.

ABSTRACT: We reported that murine tumor lysate-pulsed dendritic cells (TP-DC) could elicit tumor-specific CD4(+) and CD8(+) T cells in vitro and in vivo. In some limited cases, TP-DC treatments in vivo could also result in regression of established subcutaneous tumors and lung metastases. By gene array analysis, we reported a high level of expression of a novel member of the cell surface class A scavenger receptor family, MARCO, by murine TP-DC compared to unpulsed DC. MARCO is thought to play an important role in the immune response by mediating binding and phagocytosis, but also in the formation of lamellipodia-like structures and dendritic processes. We have now examined the biologic and therapeutic implications of MARCO expressed by TP-DC. In vitro exposure of TP-DC to a monoclonal anti-MARCO antibody resulted in a morphologic change of rounding with disappearance of dendritic-like processes. TP-DC remained viable after anti-MARCO antibody treatment; had little, if any, change in production of IL-10, IL-12p70 and TNF-alpha; but demonstrated enhanced migratory capacity in a microchemotaxis assay. The use of a selective inhibitor showed MARCO expression to be linked to the p38 mitogen-activated protein kinase (MAPK) pathway. In vivo, anti-MARCO antibody treated TP-DC showed better trafficking from the skin injection site to lymph node, enhanced generation of tumor-reactive IFN-gamma producing T cells, and improved therapeutic efficacy against B16 melanoma. These results, coupled with our finding that human monocyte-derived DC also express MARCO, could have important implications to human clinical DC vaccine trials.

SUBMITTER: Matsushita N

PROVIDER: S-EPMC2861905 | biostudies-literature | 2010 Jun

REPOSITORIES: biostudies-literature

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Targeting MARCO can lead to enhanced dendritic cell motility and anti-melanoma activity.

Matsushita Norimasa N Komine Hiroshi H Grolleau-Julius Annabelle A Pilon-Thomas Shari S Mulé James J JJ

Cancer immunology, immunotherapy : CII 20100108 6

We reported that murine tumor lysate-pulsed dendritic cells (TP-DC) could elicit tumor-specific CD4(+) and CD8(+) T cells in vitro and in vivo. In some limited cases, TP-DC treatments in vivo could also result in regression of established subcutaneous tumors and lung metastases. By gene array analysis, we reported a high level of expression of a novel member of the cell surface class A scavenger receptor family, MARCO, by murine TP-DC compared to unpulsed DC. MARCO is thought to play an importan ...[more]

PMID: 20054688

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Project description:BackgroundFarnesyltransferase inhibitors (FTIs) are anticancer agents with a spectrum of activity in Ras-dependent and independent tumor cellular and xenograph models. How inhibition of protein farnesylation by FTIs results in reduced cancer cell proliferation is poorly understood due to the multiplicity of potential FTase targets. The low toxicity and oral availability of FTIs led to their introduction into clinical trials for the treatment of breast cancer, hematopoietic malignancy, advanced solid tumor and pancreatic cancer treatment, and Hutchinson-Gilford Progeria Syndrome. Although their efficacy in combinatorial therapies with conventional anticancer treatment for myeloid malignancy and solid tumors is promising, the overall results of clinical tests are far below expectations. Further exploitation of FTIs in the clinic will strongly rely on understanding how these drugs affect global cellular activity.MethodsUsing FTase inhibitor I and genome-wide chemical profiling of the yeast barcoded deletion strain collection, we identified genes whose inactivation increases the antiproliferative action of this FTI peptidomimetic. The main findings were validated in a panel of cancer cell lines using FTI-277 in proliferation and biochemical assays paralleled by multiparametric image-based analyses.ResultsABC transporter Pdr10 or p-21 activated kinase (PAK) gene deletion increases the antiproliferative action of FTase inhibitor I in yeast cells. Consistent with this, enhanced inhibition of cell proliferation by combining group I PAK inhibition, using IPA3, with FTI-277 was observed in melanoma (A375MM), lung (A549) and colon (HT29), but not in epithelial (HeLa) or breast (MCF7), cancer cell lines. Both HeLa and A375MM cells show changes in the nuclear localization of group 1 PAKs in response to FTI-277, but up-regulation of PAK protein levels is observed only in HeLa cells.ConclusionsOur data support the view that group I PAKs are part of a pro-survival pathway activated by FTI treatment, and group I PAK inactivation potentiates the anti-proliferative action of FTIs in yeast as well as in cancer cells. These findings open new perspectives for the use of FTIs in combinatorial strategies with PAK inhibitors in melanoma, lung and colon malignancy.

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Targeting MARCO can lead to enhanced dendritic cell motility and anti-melanoma activity.

Publications

Targeting MARCO can lead to enhanced dendritic cell motility and anti-melanoma activity.

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